Core B: Integrated cellular profiling and pathway discovery ABSTRACT The advent of cellular reprogramming and the evolution of high-throughput sequencing and omic methodologies have converged to enable unbiased genome-wide profiling of human cells relevant for the study of genetically complex psychiatric disorders. This confluence of technological advances holds tremendous promise for transforming our understanding of the biological bases of these disorders. Realizing this promise, however, requires substantial material resources, expertise that spans multiple disciplines, and well-designed experiments. Our NCRCRG proposal has been organized to meet these demands and exploit state-of-the-art techniques to establish a robust iPSC-based discovery platform. The Integrated Cellular Profiling and Pathway Discovery Core (Core B) at Janssen and JHU is critical to meeting three key goals of this NCRCRG. The first is to develop reliable and robust differentiation protocols for four neural cell types implicated in major psychiatric diseases. Core B will validate the efficacy and reproducibility of differentiation to different cell types across different sites through quantitative transcriptomic analysis. The second is to identify cellular phenotypes of four disease-relevant cell types derived from iPSCs of patients with major psychiatric disorders and explore underlying molecular mechanisms. To meet this objective, Core B will perform single-cell RNA-seq analysis for each project and, further, hypothesis-driven proteomic and metabolomics analysis. The third goal is to integrate all information generated from the NCRCRG for biological pathway discovery, identification of potential biomarkers, and to reveal similarities and differences of bipolar disorder (BP) and schizophrenia (SZ) at the cellular and molecular levels. Core B will develop a bioinformatics pipeline and interact with each Project and core to achieve these goals. Core B will also work with the Administrative Core (Core A) to facilitate data sharing among all members of the NCRCRG in real time, and with Core C to contribute to high- throughput platform development.